A hyper-quiescent chromatin state formed during aging is reversed by regeneration.

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcriptional suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

A hyper-quiescent chromatin state formed during aging is reversed by regeneration.

Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach, and the first direct visualization of aged chromatin we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcription suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.

Gene body DNA hydroxymethylation restricts the magnitude of transcriptional changes during aging.

DNA hydroxymethylation (5hmC) is the most abundant oxidative derivative of DNA methylation (5mC) and is typically enriched at enhancers and gene bodies of transcriptionally active and tissue-specific genes. Although aberrant genomic 5hmC has been implicated in many age-related diseases, the functional role of the modification in aging remains largely unknown. Here, we report that 5hmC is stably enriched in multiple aged organs. Using the liver and cerebellum as model organs, we show that 5hmC accumulates in gene bodies associated with tissue-specific function and thereby restricts the magnitude of gene expression changes during aging. Mechanistically, we found that 5hmC decreases binding affinity of splicing factors compared to unmodified cytosine and 5mC, and is correlated with age-related alternative splicing events, suggesting RNA splicing as a potential mediator of 5hmC's transcriptionally restrictive function. Furthermore, we show that various age-related contexts, such as prolonged quiescence and senescence, are partially responsible for driving the accumulation of 5hmC with age. We provide evidence that this age-related function is conserved in mouse and human tissues, and further show that the modification is altered by regimens known to modulate lifespan. Our findings reveal that 5hmC is a regulator of tissue-specific function and may play a role in regulating longevity.

DNA methylation of Nuclear Factor of Activated T Cells 1 mediates the prospective relation between exposure to different traumatic event types and post-traumatic stress disorder.

The mechanisms through which exposure to differing trauma types become biologically embedded to shape the risk for post-traumatic stress disorder (PTSD) is unclear. DNA methylation (5-mC), particularly in stress-relevant genes, may play a role in this relationship. Here, we conducted path analysis using generalized structural equation modeling to investigate whether blood-derived 5-mC in Nuclear Factor of Activated T Cells 1 (NFATC1) mediates the prospective association between each of five different trauma types ("assaultive violence", "other injury or shocking experience", "learning of trauma to loved one", "sudden, unexpected death of a close friend or relative", and "other") and lifetime PTSD. All five trauma types were significantly associated with reduced methylation at NFATC1 CpG site, cg17057218. Two of the five trauma types were significantly associated with increased methylation at NFATC1 CpG site, cg22324981. Moreover, methylation at cg17057218 significantly mediated 21-32% of the total effect for four of the five trauma types, while methylation at cg22324981 mediated 27-40% of the total effect for two of the five trauma types. These CpG sites were differentially associated with transcription factor binding sites and chromatin state signatures. NFATC1 5-mC may be a potential mechanism in the relationship between some trauma types and prospective risk for PTSD.

Epigenetic dysregulation in cardiovascular aging and disease.

Cardiovascular disease (CVD) is the leading cause of mortality and morbidity for all sexes, racial and ethnic groups. Age, and its associated physiological and pathological consequences, exacerbate CVD incidence and progression, while modulation of biological age with interventions track with cardiovascular health. Despite the strong link between aging and CVD, surprisingly few studies have directly investigated heart failure and vascular dysfunction in aged models and subjects. Nevertheless, strong correlations have been found between heart disease, atherosclerosis, hypertension, fibrosis, and regeneration efficiency with senescent cell burden and its proinflammatory sequelae. In agreement, senotherapeutics have had success in reducing the detrimental effects in experimental models of cardiovascular aging and disease. Aside from senotherapeutics, cellular reprogramming strategies targeting epigenetic enzymes remain an unexplored yet viable option for reversing or delaying CVD. Epigenetic alterations comprising local and global changes in DNA and histone modifications, transcription factor binding, disorganization of the nuclear lamina, and misfolding of the genome are hallmarks of aging. Limited studies in the aging cardiovascular system of murine models or human patient samples have identified strong correlations between the epigenome, age, and senescence. Here, we compile the findings in published studies linking epigenetic changes to CVD and identify clear themes of epigenetic deregulation during aging. Pending direct investigation of these general mechanisms in aged tissues, this review predicts that future work will establish epigenetic rejuvenation as a potent method to delay CVD.

Prevalence and Factors Associated With Intimate Partner Violence Among Women in Haiti: Understanding Household, Individual, Partner, and Relationship Characteristics.

Intimate partner violence (IPV) is a significant public health issue with detrimental consequences for women's reproductive, mental, and physical health. In Haiti, IPV is a major obstacle to women's development. Yet, the determinants of IPV victimization are still not well understood. In this study, we utilized the 2016-2017 Haiti Demographic and Health Survey to determine the prevalence of IPV victimization and its subtypes (emotional, physical, and sexual abuse) among married or cohabiting women (N = 3,805) of reproductive age (15-49) by their current husband/partner. Logistic regression was conducted to explore the association between IPV and household, individual, husband/partner, and relationship characteristics. The prevalence of IPV victimization was 32.5% with the majority reporting emotional (24.7%) followed by physical (16.8%) and sexual (10.5%) violence. Increased odds of IPV victimization were found among women with children in the household (adjusted odds ratio [AOR] = 1.45, 95% confidence interval [CI] = [1.03, 2.02]), with attitudinal acceptance of wife-beating (AOR = 1.45, 95% CI = [1.05, 2.02]), and those who witnessed their father beating their mother (AOR = 1.49, 95% CI = [1.18, 2.67]). Higher odds of reporting IPV victimization were also found among women whose partner drank alcohol (AOR = 2.89, 95% CI = [2.29, 3.65]), who were in a polygynous relationship (AOR = 1.76, 95% CI = [1.23, 2.40]), and displayed one or more controlling behaviors (AOR = 1.92, 95% CI = [1.42, 2.59]). Women who reported being afraid of their partner had greater odds of IPV victimization (AOR = 16.22, 95% CI = [8.38, 31.39]). Decreased odds of reporting IPV were associated with women living in rural areas (AOR = 0.73, 95% CI = [0.53, 1.00]) and those unmarried, but living with their partner (AOR = 0.62, 95% CI = [0.43, 0.90]). Our findings identify subgroups of women in Haiti that may be vulnerable to IPV victimization. Thus, we recommend a differentiated approach to IPV prevention strategies and interventions that consider women's family structure in the household as well as individual, partner, and relationship characteristics.